This invention relates generally to novel lactam inhibitors of matrix metalloproteinases, TNF-xcex1, and aggrecanase, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production. 
EP 574,758 A1 illustrates hydroxamic acid derivatives as collagenase inhibitors having the general formula: 
GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
WO 97/32846 depicts hydroxamic acid derivatives as MMP inhibitors having the general formula: 
wherein X and Y are carbon or nitrogen, and R3 and R4 can be a variety of groups including amides, aryls, heterocycles and cycloalkyls. Compounds of this sort are not considered to be part of the present invention.
The compounds of the current invention act as inhibitors of MMPs, aggrecanase and/or TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Accordingly, one object of the present invention is to provide novel lactams which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel lactams for use in therapy.
It is another object of the present invention to provide the use of novel lactams for the manufacture of a medicament for the treatment of an inflammatory disorder.
It is another object of the present invention to provide the use of novel lactams for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R3, and R4 are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, C(RRxe2x80x2)CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94C(RRxe2x80x2)CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)C(O)R5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, SN2H2Ra, PO(OH)2, and PO(OH)NHRa;
ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Xbxe2x80x94Za;
U is absent or is selected from: NRa, C(O), C(O)O, C(O)NRa, NRaC(O), NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRa, S(O)p, and C(O);
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from O, NRa, S(O)p, and C(O);
Xb is absent or selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Za is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
provided that:
(a) when U is absent, X and Y are absent; and,
(b) R1 is other than unsubstituted alkyl, alkylene-Z, alkylene-Za, alkylene-amino-Z, alkylene-amino-Za, alkylene-amino-Z-Za, and alkylene-amino-Z-alkylene-Za;
R2 is selected from H, Qxe2x80x2, C1-10 alkylene-Qxe2x80x2, C2-10 alkenylene-Qxe2x80x2, C2-10 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, and (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
Qxe2x80x2 is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x3NHQ, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)ORa, and (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)(CRRxe2x80x2)rNHC(O)ORa,
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R4 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94H, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94H;
alternatively, R3 and R4 combine to form a C3-13 carbocyclic residue substituted with Rc and 0-3 Rb or a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with Rc and 0-3 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x3, at each occurrence, is independently selected from H, C1-4 alkyl, benzyl, C3-7 carbocyclic residue, or a 5 to 6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 4, 5, or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rd, phenyl, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from H, C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from phenyl substituted with 0-3 Rb, biphenyl substituted with 0-2 Rb, naphthyl substituted with 0-3 Rb and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, xe2x80x94CH(R8)OC(xe2x95x90O)OR9, and 
R7 selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Re, C3-8 cycloalkyl substituted with 1-2 Re, and phenyl substituted with 0-2 Rb;
Re, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
rxe2x80x3, at each occurrence, is selected from 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, 2, and 3; and,
sxe2x80x2, at each occurrence, is selected from 0, 1, 2, and 3.
In a preferred embodiment, the present invention provides a compound wherein;
A is selected from COR5, xe2x80x94CO2H, CH(R)CO2H, xe2x80x94CONHOH, CH(R)CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
U is absent;
X is absent;
Y is absent;
Z is selected from a C5-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)pNRa, and NRaS(O)p;
R2 is selected from H, Qxe2x80x2, C1-5 alkylene-Qxe2x80x2, C2-5 alkenylene-Qxe2x80x2, C2-5 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rQxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rb and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rQ, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q;
R, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rxe2x80x2, at each occurrence, is independently selected from H and CH3;
Q is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb; and,
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S.
In a more preferred embodiment, the present invention provides a compound wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, CH(R)CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 4-6 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-9 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), and S(O)pNRa;
Xa is absent or C1-10 alkylene;
R2 is selected from H, C1-5 alkylene-Qxe2x80x2, (CH2)rxe2x80x2(CH2)rxe2x80x94Qxe2x80x2, (CH2)rxe2x80x2NRa(CH2)rQxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rQxe2x80x2, (CH2)rxe2x80x2C(O)NRa(CH2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, and (CH2)rxe2x80x2C(O)(CH2)rxe2x80x94Qxe2x80x2;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-9 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; and,
Q is selected from H, a C5-6 carbocyclic residue substituted with 0-5 Rb and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb.
In an even more preferred embodiment, the present invention provides a compound wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, and xe2x80x94N(OH)CHO;
ring B is a 4-5 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
X is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Z is absent or selected from phenyl substituted with 0-3 Rb and a 5-9 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Xa is absent or C1-4 alkylene;
Ya is absent or selected from O and NRa;
Za is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R4 is selected from H, C1-4 alkylene-H, (CH2)rxe2x80x2O(CH2)rxe2x80x94H, and (CH2)rxe2x80x2NRa(CH2)rxe2x80x94H; and,
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S.
In a preferred embodiment, the present invention provides a compound wherein;
(xcex1S,3R)-xcex1-[(2,2-dimethyl-1-oxopropyl)amino]-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
1,1-dimethylethyl [2-(hydroxyamino)-(1S)-1-[1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-oxoethyl]carbamate;
(xcex1S,3R)-xcex1-amino-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
(xcex1S,3R)-xcex1-(acetylamino)-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
N-[2-(hydroxyamino)-(1S)-1-[1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-oxoethyl]-4-morpholinecarboxamide;
1,1-dimethylethyl [(1S)-1-[1-[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-(hydroxyamino)-2-oxoethyl]carbamate;
(xcex1S,3R)-xcex1-amino-1-[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]-N-hydroxy-2-oxo-3-pyrrolidineacetamide;
methyl (1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethylcarbamate;
butyl (1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethylcarbamate;
N-[(1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethyl]benzamide;
(2S)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-(1H-pyrrol-1-yl)ethanamide;
(2S)-2-(dimethylamino)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethanamide;
(2R)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)propanamide;
(2S)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)propanamide;
(2R)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)pentanamide;
(2S)-N,2-dihydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethanamide;
(1S)-1-{(3R)-1-[4-(benzyloxy)phenyl]-2-oxopyrrolidinyl}ethyl(hydroxy)formamide;
hydroxy[(1S)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethyl]formamide;
(2R,S)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypentanamide;
(2S,R)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypentanamide;
(2S,R)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypropanamide;
(2S,R)-((3S,R)-3-(dimethylamino)-1-{f4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypropanamide; and,
2-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxyacetamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel lactams of formula I for use in therapy.
In another embodiment, the present invention provides the use of novel lactams of formula I for the manufacture of a medicament for the treatment of an inflammatory disorder.
In another embodiment, the present invention provides the use of novel lactams of formula I for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Rb, then said group may optionally be substituted with up to two Rb groups and Rb at each occurrence is selected independently from the definition of Rb. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-thiazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a MMP related disorder in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of a MMP) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased inhibitory effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated herein in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein ring B is pyrrolidinone or piperidinone can be prepared by methods described in Scheme 1. Carboxylic acid 1 can be converted to 3 under several sets of literature conditions. One example is activation of 1 with trimethylacetyl chloride followed by treatment with 2. Alkylation of 3 with methyl bromoacetate or t-butyl bromoacetate provides 4a or 4b, respectively. 4a and 4b are converted to aldehydes 5a and 5b by oxidative degradation, such as ozonolysis, or dihydroxylation (OSO4) followed by cleavage with NaIO4. The desired pyrrolidinone 7a and piperidinone 7b are synthesized upon treatment of aldehyde 5 and appropriately functionalized amine 6 with zinc in acetic acid at elevated temperature. Alternatively, 5 and 6 are first coupled to form imine in toluene at reflux, then reduced with reducing agent such as sodium triacetoxyborohydride, and finally cyclized at elevated temperature. As another alternative route to 7b, 4b is hydrolyzed to give carboxylic acid 8. 8 is coupled to an appropriately substituted amine 6 by methods well described in the literature for making amide bonds, such as BOP-Cl in THF, to give compound 9. Following oxidative cleavage as described previously, the resultant aldehyde 10 is treated with reducing agents such as triethylsilane in the presence of acids such as trifluoroacetic acid to provide 7b. 
The methyl ester of 7 (R11=Me) is converted to hydroxamic acid 11 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol (Scheme 2). The methyl ester 7 (R11=Me) can also be converted to O-benzyl protected hydroxamic acid with O-benzylhydroxylamine under similar conditions or using Weinreb""s trimethylalluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on barium sulfate in hydrogen, to give compound 11. Alternatively, 11 can be prepared through the carboxylic intermediate 12. Carboxylic acid 12 is converted to 11 via coupling with hydroxylamine or O-benzylhydroxylamine followed by deprotection. 
A variety of compounds of formula (I) wherein ring B is pyrrolidinone or piperidinone and R3 is alkyl can be prepared by methods described in Scheme 3. Following known literature procedure (Becket, R. P.; Crimmins, M. J.; Davis, M. H.; Spavold, Z. Synlett 1993, 137), intermediate 8 from Scheme 1 is converted to anti-succinate 14 via alkylation and epimerization. Following esterification and olefin cleavage, the aldehyde 16 is converted to lactam 17 following conditions as described previously. Ester 17 is converted to the hydroxamic acid following the sequences outlined in Scheme 2. 
A variety of compounds of formula (I) wherein ring B is imidazolinone or piperazinone can be prepared by methods described in Scheme 4. Esterification of D-aspartic acid 18 and alkylation provide anti-alkylated product 20. Cleavage of benzyl ester, coupling with appropriately functionalized amine 6 under conditions described previously and unmasking of the amino group gives 23. The imidazolinone ring formation is achieved with formaldehyde in solvent such as toluene at elevated temperature. The piperazinone analogues can be synthesized from common intermediate 21. Following coupling with appropriately functionalized amine 25 and olefin cleavage, the aldehyde 27 is converted to piperazinone 28 following conditions as described previously. The secondary amine center of 28 is further functionalized as tertiary amines, amides, sulfonamides, carbamates, ureas, or sulfonylureas (29). Esters 24, 28 and 29 are converted to the hydroxamic acids following the sequences outlined in Scheme 2. 
A variety of compounds of formula (I) wherein R3 is an amino derivative can be prepared by methods described in Scheme 5. L-Aspartic acid 30 is converted to 32 following similar sequence described earlier. Oxidative cleavage of 32 yields aldehyde 33 (n=1), an intermediate for pyrrolidinones. The corresponding intermediate for piperidinones, 33 (n=2), is synthesized by hydroboration with agents such as 9-BBN and oxidation following methods well described in the literature, such as Swern oxidation. 33 is converted to 34 following conditions described previously. After removal of BOC group, The primary amine center of 35 is further functionalized as secondary or tertiary amines, amides, sulfonamides, carbamates, ureas, or sulfonylureas (36 and 37). Esters 34-37 are converted to the hydroxamic acids following the sequences outlined in Scheme 2. 
A variety of compounds of formula (I) wherein R3 is OR can be prepared by methods described in Scheme 6. Frater alkylation of dimethyl malate (38) establishes the anti configuration. 39 is converted to 41 using chemistry described previously. The hydroxyl group in 41 is functionalized as ethers, esters, carbonates or urethanes (42). Esters 41-42 are converted to the hydroxamic acids following the sequences outlined in Scheme 2. 
A variety of compounds of formula (I) wherein A is xe2x80x94NH(OH)C(O)H can be prepared by methods described in Scheme 7. Frater alkylation, and Wenreib amide formation with O-t-butylhydroxylamine give 45. xcex2-Lactam formation is done by mesylate formation and base-induced lactamization. TMSCl mediated methanolysis followed by N-formylation provide 49. Following sequence analogous to that described in previous schemes, lactam 51 is obtained. Hydrolysis of t-Butyl group in 51 completes the synthesis. 
A variety of compounds of formula (I) wherein R1 is functionalized phenyl group can be prepared by methods described in Scheme 8. Intermediate 53, available from schemes described previously, is converted to phenol 54 by hydrogenolysis. 54 is used as common intermediates for structure diversification. Reaction of 54 with R11xe2x80x94X provides 55, an alternative is the reaction of 54 with R11xe2x80x94OH under Mitsunobu conditions to produce 55. R10 can be appended directly to the aromatic ring by converting 54 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 56. 54 can also be reacted with acyl halides or isocyanates to afford 58. Biaryl ethers 57 can be produced by treatment of 54 with aryl boronic acids in the presence of a copper catalyst. Esters 55-58 are converted to the hydroxamic acids following the sequences outlined in Scheme 2. 
A variety of compounds of formula (I) wherein R2 is an amino derivative can be prepared by methods described in Scheme 9. Protecting group manipulations on 59 give 61. Allylation and esterification gives 63. 63 is converted to lactam 65 following previously described sequences. Allylation and hydrogenation provide phenol 67. 67 can be functionalized following scheme 8 and converted to hydroxamic acid following scheme 2. 
Aternatively, phenol 67 can be prepared following scheme 10. Allylation of 60 gives 68 with the desired anti configuration. Following hydrogenation, 69 is further allylated and protected as methyl ester. 70 is then converted to phenol 67 following previously described sequences. 
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tert. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.